TGF-beta in Mammary Development and Tumorigenesis

点击翻译按钮获取中文摘要

The importance of stromal-epithelial interactions in mammary gland development and tumorigenesis is well established. These interactions likely involve autocrine and paracrine action of multiple growth factors, including members of the TGF-13 family, which are expressed in both stroma and epithelium. We have previously demonstrated that expression of a dominant-negative type II TGF-I_ receptor construct (DNIIR) in mammary stroma using a metallothionein (MT) promoter results in increased lateral branching. Current evidence indicates that DNIIR causes only partial blockage of TGF-6 signaling. To accomplish complete knock-out of the type II TGF-I_ receptor gene (Tgfbr2) in mammary stromal cells we have crossed FSP1-Cre mice with the Tgfbr2(floxE2/floxE2) mice. FSP1 (fibroblast-specific protein-I) is expressed in stromal fibroblasts. As shown under Preliminary Studies, these mice have a phenotype different from that observed with partial abrogation of TGF-I_ signaling in stromal cells in the MT-DNIIR mice. With complete knock-out of Tgfbr2 in stromal cells there was loss of mammary fat cells with a markedly hypercellular stroma and decreased ductal branching with hypoplastic epithelial cells. Animals with FSP1-Cre and heterozygous floxed Tgfbr2 [Tgfbr2(floxE2/wt)] making them haploinsufficient for Tgfbr2 in stromal cells have normal mammary gland development, but defective regression following lactation. Thus, we have a unique model for studying the role of TGF-13 signaling in stromal cells on mammary gland development and tumorigenesis. Based on this information, we have formulated the following hypotheses: (1) TGF-13 signaling in stroma is essential for normal development of the mammary gland and plays a role in the invasive and metastatic potential of carcinoma cells. (2) Stromal haploinsufficiency of Tgfbr2 leads to incomplete regression following lactation and alters the invasion and metastatic capabilities of mammary tumors induced by co- expressed oncogenes. The Specific Aims are proposed to test these hypotheses are: 1. Characterization of Cre expression pattern, recombination and phenotype of FSP1-Cre:Tgfbr2(floxE2/floxE2) mice. 2. Characterization of Cre expression pattern, recombination and phenotype of mice haploinsufficient for Tgfbr2 in stroma, FSP1-Cre:Tgfbr2(floxE2/wt) mice. 3. Characterization of Tgfbr2 null stromal cells and determination of their effect on invasion and metastasis of carcinoma cells.